NM_001042545.2:c.1702C>G

Variant names:

• chr19-40610549-C-G
• rs33937741
• NM_001042545.2:c.1702C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001042545.2(LTBP4):​c.1702C>G​(p.Arg568Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0417 in 1,593,254 control chromosomes in the GnomAD database, including 1,658 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R568P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.029 (82 hom., cov: 33)
  • Exomes 𝑓: 0.043 (1576 hom.)
• Consequence: LTBP4 NM_001042545.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.126
• Publications: 9 publications found

Genes affected

LTBP4 (HGNC:6717): (latent transforming growth factor beta binding protein 4) The protein encoded by this gene binds transforming growth factor beta (TGFB) as it is secreted and targeted to the extracellular matrix. TGFB is biologically latent after secretion and insertion into the extracellular matrix, and sheds TGFB and other proteins upon activation. Defects in this gene may be a cause of cutis laxa and severe pulmonary, gastrointestinal, and urinary abnormalities. Three transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, May 2010]

LTBP4 Gene-Disease associations (from GenCC):

• cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003421694).
• BP6: Variant 19-40610549-C-G is Benign according to our data. Variant chr19-40610549-C-G is described in ClinVar as Benign. ClinVar VariationId is 329310.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0288 (4385/152318) while in subpopulation NFE AF = 0.0456 (3105/68032). AF 95% confidence interval is 0.0443. There are 82 homozygotes in GnomAd4. There are 2005 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 82 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001042545.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LTBP4	NM_001042545.2	MANE Select	c.1702C>G	p.Arg568Gly	missense	Exon 12 of 30	NP_001036010.1
	LTBP4	NM_001042544.1		c.1903C>G	p.Arg635Gly	missense	Exon 15 of 33	NP_001036009.1
	LTBP4	NM_003573.2		c.1792C>G	p.Arg598Gly	missense	Exon 15 of 33	NP_003564.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LTBP4	ENST00000396819.8	TSL:1 MANE Select	c.1702C>G	p.Arg568Gly	missense	Exon 12 of 30	ENSP00000380031.5
	LTBP4	ENST00000308370.11	TSL:1	c.1903C>G	p.Arg635Gly	missense	Exon 15 of 33	ENSP00000311905.8
	LTBP4	ENST00000204005.13	TSL:1	c.1792C>G	p.Arg598Gly	missense	Exon 15 of 33	ENSP00000204005.10

Frequencies

GnomAD3 genomes AF: 0.0288 AC: 4387 AN: 152200 Hom.: 82 Cov.: 33

Gnomad AFR AF: 0.00864

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0219

Gnomad ASJ AF: 0.0228

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00806

Gnomad FIN AF: 0.0395

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0457

Gnomad OTH AF: 0.0220

GnomAD2 exomes AF: 0.0275 AC: 5921 AN: 215696 AF XY: 0.0277

Gnomad AFR exome AF: 0.00775

Gnomad AMR exome AF: 0.0133

Gnomad ASJ exome AF: 0.0229

Gnomad EAS exome AF: 0.0000593

Gnomad FIN exome AF: 0.0408

Gnomad NFE exome AF: 0.0429

Gnomad OTH exome AF: 0.0294

GnomAD4 exome AF: 0.0431 AC: 62133 AN: 1440936 Hom.: 1576 Cov.: 32 AF XY: 0.0421 AC XY: 30184 AN XY: 716438

African (AFR) AF: 0.00719 AC: 240 AN: 33370

American (AMR) AF: 0.0143 AC: 619 AN: 43168

Ashkenazi Jewish (ASJ) AF: 0.0227 AC: 587 AN: 25904

East Asian (EAS) AF: 0.000102 AC: 4 AN: 39402

South Asian (SAS) AF: 0.0116 AC: 984 AN: 84800

European-Finnish (FIN) AF: 0.0436 AC: 1791 AN: 41084

Middle Eastern (MID) AF: 0.00729 AC: 42 AN: 5760

European-Non Finnish (NFE) AF: 0.0503 AC: 55746 AN: 1107546

Other (OTH) AF: 0.0354 AC: 2120 AN: 59902

GnomAD4 genome AF: 0.0288 AC: 4385 AN: 152318 Hom.: 82 Cov.: 33 AF XY: 0.0269 AC XY: 2005 AN XY: 74480

African (AFR) AF: 0.00861 AC: 358 AN: 41568

American (AMR) AF: 0.0219 AC: 335 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0228 AC: 79 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00807 AC: 39 AN: 4832

European-Finnish (FIN) AF: 0.0395 AC: 419 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0456 AC: 3105 AN: 68032

Other (OTH) AF: 0.0218 AC: 46 AN: 2114

Alfa AF: 0.0311 Hom.: 37

Bravo AF: 0.0273

TwinsUK AF: 0.0547 AC: 203

ALSPAC AF: 0.0527 AC: 203

ESP6500AA AF: 0.00630 AC: 26

ESP6500EA AF: 0.0420 AC: 351

ExAC AF: 0.0254 AC: 3060

Asia WGS AF: 0.00462 AC: 16 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies (1)
-	-	1	LTBP4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.17	T
MetaRNN	Benign	0.0034	T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	0.43	N
PhyloP100		0.13
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.25
Sift	Uncertain	0.011	D
Sift4G	Benign	0.28	T
Polyphen		0.83	P
Vest4		0.47
MPC		1.0
ClinPred		0.042	T
GERP RS		2.8
Varity_R		0.27
gMVP		0.60
Mutation Taster		=93/7	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs33937741; hg19: chr19-41116455; COSMIC: COSV107219832; COSMIC: COSV107219832;